Acetobenzylamide piperazine derivative and application thereof as cranial nerve protective agent

A technology of acetylbenzylamine piperazine and derivatives, which is applied in the field of acetylbenzylamine piperazine derivatives, can solve the problems of difficult to pass through the blood-brain barrier, low activity, high cardiotoxicity, etc., and achieve significant hypoxia resistance activity, High activity and few side effects

Active Publication Date: 2016-03-23
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved in the present invention is to disclose a class of acetylbenzylamine piperazine derivatives and their application as brain neuroprotective agents to overcome the low activity of existing anti-stroke drugs and difficulty in penetrating the blood-brain barrier, cardiac Defects such as high toxicity;

Method used

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  • Acetobenzylamide piperazine derivative and application thereof as cranial nerve protective agent
  • Acetobenzylamide piperazine derivative and application thereof as cranial nerve protective agent
  • Acetobenzylamide piperazine derivative and application thereof as cranial nerve protective agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] N-Benzyl-2-(4-{2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-carbonylethyl}piperazin-1-yl) Acetamide (V-1) and its hydrochloride

[0084] Put 2-amino-5-methyl-3,4-diazathiophene (20mmol), chloroacetyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, follow General Method 2 N-(5-methyl-3,4-diazathiophene)-2-chloroacetamide was obtained with a yield of 67%.

[0085] The above-obtained N-(5-methyl-3,4-diazathiophene)-2-chloroacetamide (12.8mmol) and N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) were put into 30ml acetone solution, add K 2 CO 3 (19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain the free base N-benzyl-2-(4-{2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-carbonyl ethyl Bas...

Embodiment 2

[0090] [4-(2-Benzylamino-2-carbonylethyl)piperazin-1-yl]-N-phenylpropanamide (V-2) and its hydrobromide

[0091] Put aniline (20mmol), 2-chloropropionyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, and follow the operation of General Method 2 to obtain N-aniline-2-chloropropane Amide, yield 66%.

[0092] Put the N-aniline-2-chloropropionamide (12.8mmol) obtained above and the N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) into 30ml of acetone solution, and add K 2 CO 3(19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain the free base [4-(2-benzylamino-2-carbonylethyl)piperazin-1-yl]-N-phenylpropanamide (V-2), 4.0g, yield 81.87%.

[0093] Add 8ml of ethanol to the free base and heat to ...

Embodiment 3

[0097] 2-[4-(2-Benzylamino-2-carbonylethyl)piperazin-1-yl]-N-(4-methoxyphenyl)propionamide (V-3) and its sulfate;

[0098] Put p-methoxyaniline (20mmol), 2-chloropropionyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, and follow the operation of General Method 2 to obtain N-p-methyl Oxyaniline-2-chloropropionamide, yield 64%.

[0099] The above-obtained N-p-methoxyaniline-2-chloropropionamide (12.8mmol) and N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) were put into 30ml of acetone solution, and K 2 CO 3 (19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain free base 2-[4-(2-benzylamino-2-carbonylethyl)piperazin-1-yl]-N-(4-methoxyphenyl)propionamide (V -3), 3.4g, yield 64.63%.

[0100] ...

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Abstract

The invention discloses an acetobenzylamide piperazine derivative and an application thereof as a cranial nerve protective agent. Pharmacological experiments verify that the compound disclosed by the invention shows an obvious effect against glutamic acid-induced neuron exitotoxicity in vitro and obvious anti-anoxia activity in a mouse, and a herg test further shows that the compound disclosed by the invention does not have the risk of cardiotoxicity. Therefore, the compound disclosed by the invention has the advantages of being high in activity, less in side effect and good in druggability. The compound and a medicinal preparation thereof have a good curative effect for treating cranial nerve injury diseases, for example, stroke and related diseases and do not have the risk of cardiotoxicity. The acetobenzylamide piperazine derivative is a free alkali or salt of a compound with a chemical structural formula shown in the description.

Description

technical field [0001] The invention relates to a class of acetylbenzylamine piperazine derivatives and the use of the compound as a protective agent for cranial nerves. Background technique [0002] Stroke (especially ischemic stroke) is a common disease with high morbidity, high mortality, and high disability rate, which has seriously threatened the health of the general public. Stroke is currently the third leading cause of death in humans, second only to cancer and myocardial infarction. According to the statistics of the World Health Organization, the global stroke mortality rate is about 4.6 million people / year, and in my country: about 1.5 million people / year. It is estimated that in the next ten years, 15 million people in my country will face the threat of stroke death. Stroke is also the number one factor leading to long-term severe loss of self-care ability. There are about 5 million stroke survivors in my country, 75% of whom are disabled to varying degrees, an...

Claims

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Application Information

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IPC IPC(8): C07D231/22C07D417/12C07D285/135C07D295/15C07D235/02C07D209/34C07D235/26C07D231/40C07D213/75A61K31/496A61K31/454A61P25/00A61P9/10
Inventor 李建其翁志洁崔宁解鹏马潇
Owner SHANGHAI INST OF PHARMA IND
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